SUMMARY FOR CLINICAL CORE The over-arching goal of the Clinical Core will be to provide research diagnostic evaluations for a large clinical population with a special emphasis on subjects who are followed longitudinally to provide well- characterized subjects for the research projects conducted by ADRC investigators and collaborators. Important focuses of the Clinical Core as for the Yale ADRC broadly include cell biology, the integration of translational neuroscience, and an emphasis on systematic storage of biospecimens for current and future biomarker studies. While the importance of biomarkers for Alzheimer's disease (AD) diagnosis and therapeutic development is well appreciated, recent advances in targeted proteomics have not been deployed in this field. The Yale ADRC Biomarker/Pathology Core and specific Research Projects will seek to develop these methods with relevance to AD and related disorders. In partnership with these efforts, the Clinical Core will undertake the collection of a wide range of biomarker specimens across the full spectrum of AD cross-sectionally and during the full course of AD longitudinally. Aim 1 will provide for the evaluation and enrollment of approximately 500 subjects who will enter the Core Population for participation in research in five diagnostic categories on the full continuum of AD (from preclinical to dementia), as well as non-AD dementias and normal controls. A diagnostic category of special interest for the Yale ADRC is cognitively normal middle-aged (50-65) first-degree relatives at varying APOE4 genetic risk for AD. Aim 2 will enroll these 500 subjects in the Uniform Data Set (UDS) population and make the UDS measures available to the National Alzheimer's Coordinating Center (NACC) for national studies. Aim 3 will enroll subjects into the Autopsy Program. Aim 4 will provide appropriate subjects for the clinical studies affiliated with the ADRC. Aim 5 will collect and distribute biological specimens to ADRC and other researchers for biomarker studies. These Aims will provide ADRC affiliated investigators the ready ability to test biomarkers once validated in AD dementia in the earliest stages of AD pathogenesis.